Key points Remote ischaemic preconditioning (RIPC), induced by brief bouts of ischaemia followed by reperfusion, confers vascular adaptations that protect against subsequent bouts of ischaemia; however, the effect of RIPC repeated over several days on the human microcirculation is unknown. Using skin as a model, microvascular function was assessed at a control and a NO‐inhibited area of skin before 1 day after and 1 week after administering seven consecutive days of repeated RIPC on the contralateral arm. Maximal vasodilatation was increased by ∼20–50% following 7 days of repeated RIPC, and this response remained elevated 1 week after stopping RIPC; however, NO‐mediated vasodilatation was not affected by the RIPC stimulus. These data indicate that repeated RIPC augments maximal vasodilatation, but the underlying mechanism for this improvement is largely independent of NO. This finding suggests a role for other endothelium‐derived mediators and/or for endothelium‐independent adaptations with repeated RIPC. Abstract Remote ischaemic preconditioning (RIPC), induced by intermittent periods of ischaemia followed by reperfusion, confers cardiovascular protection from subsequent ischaemic bouts. RIPC increases conduit and resistance vessel function; however, the effect of RIPC on the microvasculature remains unclear. Using human skin as a microvascular model, we hypothesized that cutaneous vasodilatory (VD) function elicited by localized heating would be increased following repeated RIPC. Ten participants (23 ± 1 years, 6 males, 4 females) performed RIPC for seven consecutive days. Each daily RIPC session consisted of 4 repetitions of 5 min of arm blood flow occlusion interspersed by 5 min reperfusion. Before, 1 day after and 1 week after the 7 days of RIPC, two microdialysis fibres were placed in ventral forearm skin for continuous infusion of Ringer solution or 20 mM l‐NAME. Red blood cell flux was measured by laser Doppler flowmetry at each fibre site during local heating (Tloc = 39°C) and during maximal VD elicited by heating (Tloc = 43°C) and 28 mM sodium nitroprusside infusion. Data were normalized to cutaneous vascular conductance (flux/mmHg). Seven days of RIPC did not alter the nitric oxide (NO) contribution to the VD response to local heating (P > 0.05). However, the maximal VD was augmented (Pre: 2.5 ± 0.2, Post: 3.8 ± 0.5 flux/mmHg; P < 0.05) and remained elevated 1 week post RIPC (3.3 ± 0.4 flux/mmHg; P < 0.05). Repeated RIPC improves maximal VD but does not affect NO‐mediated VD in the cutaneous microvasculature. This finding suggests that other factors may explain the vasodilatory adaptations that occur following repeated RIPC.

In this study, the characteristics of total water-soluble organic carbon (WSOC) and isolated WSOC fractions were examined to gain a better understanding of the pathway of organic aerosol production. 24 h PM(2.5) samples were collected during the summer (July 28-August 28, 2009) at an urban site in Korea. A glass column filled with XAD7HP resin was used to separate the filtered extracts into hydrophilic (WSOC(HPI)) and hydrophobic (WSOC(HPO)) fractions. The origins of air mass pathways arriving at the sampling site were mostly classified into three types, those originating over the East Sea of Korea that passed over the eastern inland urban and industrial regions (type I); those from the marine (western/southwestern/southern marine) and passed over the national industrial complex regions (type II); and those from northeastern China that passed through North Korea and metropolitan areas of South Korea (type III). Measurements showed an increase in the average WSOC fraction of total OC from the type II to III air mass (53 to 64%) periods. Also, higher SO(4)(2-)/SO(x) (=SO(2) + SO(4)(2-)) was observed in the type III air mass (0.70) than those in the types I (0.49) and II (0.43). According to the average values of WSOC/OC and SO(4)(2-)/SO(x), measurements suggest that the aerosols collected during the type III air mass period were more aged or photo-chemically processed than those during the types I and II air mass periods. The relationship between the SO(4)(2-)/SO(x) and WSOC/OC (R(2) = 0.64) suggests that a significant fraction of the observed WSOC at the site could be formed by an oxidation process similar to SO(4)(2-) aerosols, probably the oxidation process using OH radicals, or in-cloud processing. The photochemical production of WSOC(HPO) was also observed to significantly contribute to the total OC.

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. Voluntary wheel running augments aortic L-arginine transport and endothelial function in rats with chronic kidney disease. Am J Physiol Renal Physiol 307: F418 -F426, 2014. First published June 25, 2014 doi:10.1152/ajprenal.00014.2014.-Reduced nitric oxide (NO) synthesis contributes to risk for cardiovascular disease in chronic kidney disease (CKD). Vascular uptake of the NO precursor L-arginine (ARG) is attenuated in rodents with CKD, resulting in reduced substrate availability for NO synthesis and impaired vascular function. We tested the effect of 4 wk of voluntary wheel running (RUN) and/or ARG supplementation on endotheliumdependent relaxation (EDR) in rats with CKD. Twelve-week-old male Sprague-Dawley rats underwent 5 ⁄6 ablation infarction surgery to induce CKD, or SHAM surgery as a control. Beginning 4 wk following surgery, CKD animals either remained sedentary (SED) or received one of the following interventions: supplemental ARG, RUN, or combined RUNϩARG. Animals were euthanized 8 wk after surgery, and EDR was assessed. EDR was significantly impaired in SED vs. SHAM animals after 8 wk, in response to ACh (10 Ϫ9 -10 Ϫ5 M) as indicated by a reduced area under the curve (AUC; 44.56 Ϯ 9.01 vs 100 Ϯ 4.58, P Ͻ 0.05) and reduced maximal response (Emax; 59.9 Ϯ 9.67 vs. 94.31 Ϯ 1.27%, P Ͻ 0.05). AUC was not improved by ARG treatment but was significantly improved above SED animals in both RUN and RUNϩARG-treated animals. Maximal relaxation was elevated above SED in RUNϩARG animals only. L-[ 3 H]arginine uptake was impaired in both SED and ARG animals and was improved in RUN and RUNϩARG animals. The results suggest that voluntary wheel running is an effective therapy to improve vascular function in CKD and may be more beneficial when combined with L-arginine. endothelial dysfunction; chronic kidney disease; L-arginine; exercise ENDOTHELIAL DYSFUNCTION CONTRIBUTES to the development of cardiovascular disease (CVD) in patients with chronic kidney disease (CKD) and is primarily associated with a decrease in nitric oxide (NO) production and impaired endothelium-dependent relaxation (EDR) (32). The decline in endothelial function precedes the development of atherosclerosis (17, 48) and has been extensively studied as a potential therapeutic target to treat CVD; however, the specific mechanisms of endothelial dysfunction in CKD have not been fully elucidated. Patients with CKD are more likely to die of CVD than progress to end-stage renal disease (26, 42); therefore, novel treatments to improve endothelial function in CKD are needed to reduce CVD-related mortality in CKD.Insufficient availability of the NO precursor L-arginine likely contributes to reduced NO synthesis in CKD (6). Interestingly, the use of L-arginine in studies of endothelial dysfunction in late-stage CKD has produced mixed results (7, 16) unlike other conditions where it has been largely effective (8,13,15,24). Evidence from cell culture studies suggests that urea and other uremic toxins inhibit L-arginine uptake into endothelial cells (52, 54) by...

Inflammation coincides with diminished marrow function, vasodilation of blood vessels, and bone mass. Intermittent parathyroid hormone (PTH) administration independently improves marrow and vascular function, potentially impacting bone accrual. Currently, the influence of marrow and intermittent PTH administration on aged bone blood vessels has not been examined. Vasodilation of the femoral principal nutrient artery (PNA) was assessed in the presence and absence of marrow. Furthermore, we determined the influence of PTH 1-34 on 1) endothelium-dependent vasodilation and signaling pathways [i.e., nitric oxide (NO) and prostacyclin (PGI)], 2) endothelium-independent vasodilation, 3) cytokine production by marrow cells, and 4) bone microarchitecture and bone static and dynamic properties. Young (4-6 mo) and old (22-24 mo) male Fischer-344 rats were treated with PTH 1-34 or a vehicle for 2 wk. In the absence and presence of marrow, femoral PNAs were given cumulative doses of acetylcholine, with and without the NO and PGI blockers, and diethylamine NONOate. Marrow-derived cytokines and bone parameters in the distal femur were assessed. Exposure to marrow diminished endothelium-dependent vasodilation in young rats. Reduced bone volume and NO-mediated vasodilation occurred with old age and were partially reversed with PTH. Additionally, PTH treatment in old rats restored endothelium-dependent vasodilation in the presence of marrow and augmented IL-10, an anti-inflammatory cytokine. Endothelium-independent vasodilation was unaltered, and PTH treatment reduced osteoid surfaces in old rats. In conclusion, the marrow microenvironment reduced vascular function in young rats, and PTH treatment improved the marrow microenvironment and vasodilation with age. NEW & NOTEWORTHY This study investigated the influence of the marrow microenvironment on bone vascular function in young and old rats. An inflamed marrow microenvironment may reduce vasodilator capacity of bone blood vessels, diminishing delivery of blood flow to the skeleton. In young rats, the presence of the marrow reduced vasodilation in the femoral principal nutrient artery (PNA). However, intermittent parathyroid hormone administration (i.e., a treatment for osteoporosis) improved the marrow microenvironment and vasodilator capacity in old PNAs.

One week of daily remote ischemic preconditioning (RIPC) improves cutaneous vasodilatory (VD) function. However, the underlying mechanisms and the number of sessions needed to optimize this adaptive response remain unclear. We hypothesized that the responses to localized heating of the skin will be greater after 2 wk as opposed to 1 wk of RIPC. Furthermore, 2 wk of repeated RIPC will augment cutaneous VD responses to thermal and pharmacological stimuli. In methods, twenty-four participants (24 ± 2 yr; 13 men, 11 women) performed repeated RIPC (7 daily sessions over 1 wk, n = 11; 12 sessions over 2 wk, n = 13), consisting of four repetitions of 5 min of arm blood flow occlusion separated by 5 min reperfusion. Laser speckle contrast imaging was used to measure skin blood flow responses, in perfusion units (PU), to local heating (Tloc = 42°C), acetylcholine (ACh), and sodium nitroprusside (SNP) before and after repeated RIPC. Data were expressed as cutaneous vascular conductance (CVC, in PU/mmHg). In results, the VD response to local heating increased after RIPC (∆CVC from baseline; 1 wk: 0.94 ± 0.11 to 1.19 ± 0.15, 2 wk: 1.18 ± 0.07 to 1.33 ± 0.10 PU/mmHg; P < 0.05) but the ∆CVC did not differ between weeks. SNP-induced VD increased after 2 wk of RIPC (∆CVC; 0.34 ± 0.07 to 0.63 ± 0.11 PU/mmHg; P < 0.05), but ACh-induced VD did not. In conclusion, repeated RIPC improves local heating- and SNP-mediated cutaneous VD. When compared with 1 wk of RIPC, 2 wk of RIPC does not induce further improvements in cutaneous VD function. NEW & NOTEWORTHY Repeated RIPC increases the cutaneous vasodilatory response to local heating and to sodium nitroprusside but not to acetylcholine. Thus, endothelial-independent and local heating-mediated cutaneous vasodilation are improved following RIPC. However, 2 wk of RIPC sessions are not more effective than 1 wk of RIPC sessions in enhancing local heating-mediated cutaneous vasodilation.

Remote ischaemic preconditioning (RIPC) induces protective effects from ischaemiareperfusion injury. In the myocardium and conduit vasculature, a single bout of RIPC confers delayed protection that begins 24 h afterwards and lasts for 2-3 days.However, the extent and the time line in which a single bout of RIPC affects the human microvasculature are unclear. We hypothesized that a single bout of RIPC results in a delayed increase in skin microvascular function. Sixteen healthy participants (age, 23 ± 4 years; seven males, nine females; MAP, 82 ± 7 mmHg) were recruited to measure cutaneous microvascular function immediately before a single bout of RIPC and 24, 48 and 72 h and 1 week after the bout. The RIPC consisted of four repetitions of 5 min of arm blood flow occlusion interspersed by 5 min reperfusion.Skin blood flow responses to local heating (local temperature of 42 • C), ACh and sodium nitroprusside were measured by laser speckle contrast imaging and expressed as the cutaneous vascular conductance (CVC; in perfusion units per millimetre of mercury).Vasodilatation in response to local heating was increased 24 and 48 h after RIPC (ΔCVC, 1.05 ± 0.07 vs. 1.18 ± 0.07 and 1.24 ± 0.08 PU mmHg −1 , pre-vs. 24 and 48 h post-RIPC; P < 0.05). Acetylcholine-induced cutaneous vasodilatation increased significantly 48 h after RIPC (ΔCVC, 0.71 ± 0.07 vs. 0.93 ± 0.12 PU mmHg −1 , pre-vs. 48 h post-RIPC; P < 0.05) and returned to baseline thereafter. Sodium nitroprussidemediated vasodilatation did not change. Thus, a single bout of RIPC elicited a delayed response in the microvasculature, resulting in an improvement in the endotheliumdependent cutaneous vasodilatory response that peaked ∼48 h post-RIPC.

New Findings What is the central question of this study?Delayed cardiovascular responses occur following a single bout of remote ischaemic preconditioning (RIPC). Is heart rate variability (HRV), a surrogate marker of cardiac vagal control, able to detect a delayed effect after a single bout of RIPC? Do repeated bouts of RIPC further alter HRV? What is the main finding and its importance?Indices of HRV indicated a shift in sympathovagal balance toward greater parasympathetic activity following 2 weeks of RIPC but not after a single bout of RIPC. Thus, repeated bouts of RIPC were necessary to elicit changes in autonomic function. Abstract Remote ischaemic preconditioning (RIPC), induced by brief periods of ischaemia followed by reperfusion, protects against ischaemia–reperfusion injury and improves microvascular function. However, the effect of RIPC on autonomic function remains unclear. We hypothesized that RIPC, administered as a single bout or repeated over a 2‐week period, will increase markers of cardiac vagal control measured by heart rate variability (HRV). Thirty‐two young adults performed a single bout (n = 13), repeated bouts (n = 11), or served as a time control (n = 8). RIPC sessions consisted of four repetitions of 5 min unilateral brachial artery occlusion interspersed by 5 min of reperfusion. For the single bout protocol, resting lead II electrocardiogram (ECG) was collected before and 24, 48, 72 and 168 h post‐RIPC. The repeated bout protocol consisted of three 4‐day periods of RIPC training, each interspersed by a 1‐day break. Similar to time controls, ECG was collected before and 24 h after the last RIPC bout. HRV was analysed by power spectral density and symbolic dynamics using 350‐beat ECG segments. After a single bout of RIPC, no changes in HRV were observed at any time point (P > 0.05). After 2 weeks of repeated RIPC, the percentage of zero‐variation fragments (baseline = 13.1 ± 1.9%, post‐RIPC = 6.9 ± 1.5%, P < 0.05) and the LF/HF ratio decreased (baseline = 1.1 ± 0.2, post‐RIPC = 0.7 ± 0.1, P < 0.01), whereas the percentage of two‐variation fragments increased (baseline = 42.9 ± 3.6%, post‐RIPC = 52.5 ± 3.0%, P < 0.01). These data indicate that repeated RIPC is necessary to elicit changes in sympathovagal balance, specifically resulting in increased vagal and decreased sympathetic activity.